Eight deaths and dozens of drug-induced liver injury (DILI) cases have been linked to a medication the US Food & Drug Administration (FDA) wants pulled from the market, but the drug company refuses to withdraw its vasculitis treatment, reports MedPage Today.
On Tuesday, the FDA warned that post-marketing data has turned up dozens of serious cases of DILI associated with avacopan (Tavneos), a drug used to treat ANCA-associated vasculitis.
Eight of the cases were fatal, including three patients who developed vanishing bile duct syndrome (VBDS), which can lead to permanent liver damage where the bile ducts are progressively destroyed before disappearing altogether.
“Although hepatotoxicity is a serious adverse reaction for Tavneos identified in premarket clinical trials and described in product labelling, VBDS and DILI cases with fatal outcomes represent new safety concerns,” the FDA said in its safety communication.
Avacopan was approved in 2021 as an adjunctive treatment for adults with severe anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis).
The oral complement 5a inhibitor is typically used in combination with glucocorticoids and other standard medications.
FDA’s review of post-marketing data globally until October 2024 turned up 76 DILI cases with enough evidence to suggest a causal link to avacopan, including 54 hospitalisations and five US cases. Median time to DILI onset was 46 days (range 22-140).
Seven biopsy-confirmed VBDS cases were reported, all requiring hospitalisation. Initial signs and symptoms of VBDS often include jaundice, fatigue, and pruritus.
The pattern of liver injury for 38 of the DILI cases was cholestatic or mixed, often with substantial elevations in alkaline phosphatase (ALP) and total bilirubin, while the pattern in the VBDS cases was cholestatic or mixed for four patients and hepatocellular for three patients.
According to the FDA, physicians treating with avacopan should conduct regular liver panel testing and discontinue if patients develop symptomatic cholestasis or if liver enzymes spike to over three times the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase or over two times the ULN for ALP.
“If liver test abnormalities or symptoms of liver injury do not improve, patients should be referred to a hepatologist for further evaluation,” the agency said.
In January, the FDA had asked that avacopan be voluntarily withdrawn from the market, raising concerns about cases of liver injury as well as the trial data underpinning its approval, but drugmaker Amgen rebuffed the agency’s request.
On Tuesday, Amgen reiterated that it does not intend to withdraw avacopan from the market.
“Patient safety always comes first, and we are in regular communication with the FDA about the safety of our medicines,” a spokesperson said in a statement, adding that in 2024, the company had contacted the agency and proposed adding VBDS to the drug’s labelling based on cases observed outside the US, “a request that is still pending”.
“We remain confident that Tavneos is an important and effective medicine for severe active ANCA-associated vasculitis based on robust clinical data and real-world evidence demonstrating the effectiveness and favourable benefit-risk profile,” the spokesperson added.
Avacopan was approved primarily off findings from the ADVOCATE trial, which randomised patients to either avacopan or prednisone tapering with standard therapy in each arm (cyclophosphamide or rituximab).
In the phase III study, remission at week 26 was observed in 72.3% of the avacopan group and in 70.1% of the prednisone group, meeting criteria for non-inferiority. Sustained remission at week 52 was observed in 65.7% of the avacopan group and in 54.9% of the prednisone group, which was significant for both non0inferiority and superiority.
Serious adverse events related to liver-function testing occurred in 5.4% of patients in the avacopan group and in 3.7% of those in the prednisone group.
Robert Steinbrook, MD, Director of Public Citizen’s Health Research Group, said the FDA’s safety communication raises a number of questions.
“Why does the prescribing information for avacopan not include a boxed warning for the risk of fatal liver disease?” he said. “Does the FDA have data to establish that its recommendations for close monitoring of patients taking avacopan will prevent severe or fatal drug-induced liver injury? The FDA and Amgen must promptly answer these urgent questions.”
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